The E3 Ubiquitin Ligase Siah2 Contributes to Castration-Resistant Prostate Cancer by Regulation of Androgen Receptor Transcriptional Activity
ABSTRACT Understanding the mechanism underlying the regulation of the androgen receptor (AR), a central player in the development of castration-resistant prostate cancer (CRPC), holds promise for overcoming the challenge of treating CRPC. We demonstrate that the ubiquitin ligase Siah2 targets a select pool of NCOR1-bound, transcriptionally-inactive AR for ubiquitin-dependent degradation, thereby promoting expression of select AR target genes implicated in lipid metabolism, cell motility, and proliferation. Siah2 is required for prostate cancer cell growth under androgen-deprivation conditions in vitro and in vivo, and Siah2 inhibition promotes prostate cancer regression upon castration. Notably, Siah2 expression is markedly increased in human CRPCs. Collectively, we find that selective regulation of AR transcriptional activity by the ubiquitin ligase Siah2 is important for CRPC development.
Full-textDOI: · Available from: William Placzek, Feb 10, 2014
- SourceAvailable from: Qinlong li
[Show abstract] [Hide abstract]
- "The normal prostatic epithelial PrEC cells were purchased from Lonza (Allendale, NJ). The human PCa cell lines C4-2, ARCaP E and ARCaP M were established by our laboratory [13e15], and the murine prostate cancer cell line MPC3 was kindly provided by Dr. Neil Bhowmick (Cedars-Sinai Medical Center, Los Angeles, CA) . For hypoxia treatment , cells were grown in a hypoxic chamber (1% O 2 , 5% CO 2 ). "
ABSTRACT: Near-infrared fluorescence (NIRF) imaging agents are promising tools for noninvasive cancer imaging. Here, we explored the mechanistic properties of a specific group of NIR heptamethine carbocyanines including MHI-148 dye we identified and synthesized, and demonstrated these dyes to achieve cancer-specific imaging and targeting via a hypoxia-mediated mechanism. We found that cancer cells and tumor xenografts exhibited hypoxia-dependent MHI-148 dye uptake in vitro and in vivo, which was directly mediated by hypoxia-inducible factor 1α (HIF1α). Microarray analysis and dye uptake assay further revealed a group of hypoxia-inducible organic anion-transporting polypeptides (OATPs) responsible for dye uptake, and the correlation between OATPs and HIF1α was manifested in progressive clinical cancer specimens. Finally, we demonstrated increased uptake of MHI-148 dye in situ in perfused clinical tumor samples with activated HIF1α/OATPs signaling. Our results establish these NIRF dyes as potential tumor hypoxia-dependent cancer-targeting agents and provide a mechanistic rationale for continued development of NIRF imaging agents for improved cancer detection, prognosis and therapy.Biomaterials 06/2014; 35. DOI:10.1016/j.biomaterials.2014.05.073 · 8.31 Impact Factor
[Show abstract] [Hide abstract]
- "AR protein levels and functions are subjected to regulation by various posttranslational modifications including phosphorylation , acetylation, methylation, SUMOylation, and ubiquitination (van der Steen et al., 2013). Several E3 ubiquitin ligases, including MDM2, CHIP, RNF6, and SIAH2, have been found to bind to AR and play important roles in either promoting AR degradation or activating AR under various cellular conditions (He et al., 2004; Lin et al., 2002; Qi et al., 2013; Xu et al., 2009). Our identification of SPOP as a bona fide E3 ligase of the AR is highly relevant to prostate cancer, because SPOP-mediated degradation of AR protein is disrupted by its mutations identified in prostate cancer, as well as the majority of prostate cancerderived AR splicing variants. "
ABSTRACT: The SPOP E3 ubiquitin ligase gene is frequently mutated in human prostate cancers. Here, we demonstrate that SPOP recognizes a Ser/Thr-rich degron in the hinge domain of androgen receptor (AR) and induces degradation of full-length AR and inhibition of AR-mediated gene transcription and prostate cancer cell growth. AR splicing variants, most of which lack the hinge domain, escape SPOP-mediated degradation. Prostate-cancer-associated mutants of SPOP cannot bind to and promote AR destruction. Furthermore, androgens antagonize SPOP-mediated degradation of AR, whereas antiandrogens promote this process. This study identifies AR as a bona fide substrate of SPOP and elucidates a role of SPOP mutations in prostate cancer, thus implying the importance of this pathway in resistance to antiandrogen therapy of prostate cancer.Cell Reports 02/2014; 6(4). DOI:10.1016/j.celrep.2014.01.013 · 8.36 Impact Factor
[Show abstract] [Hide abstract]
- "Our inability to detect binding of endogenous NCoR1 to CREB in the absence of crosslinking may reflect the short duration of this interaction at steady state. Further studies are needed to examine how different physiological conditions impact the NCoR1/CREB complex and how Siah2 achieves specificity for the removal of NCoR1 in a subset of genes, a phenomenon that was recently exemplified by the role of this E3 ligase in gene-selective androgen receptor regulation (Qi et al., 2013). As an adaptor molecule, NCoR1 is involved in HDAC recruitment (You et al., 2013) and other mechanisms of transcriptional control (Zhou et al., 2008). "
ABSTRACT: Transcription factor activity and turnover are functionally linked, but the global patterns by which DNA-bound regulators are eliminated remain poorly understood. We established an assay to define the chromosomal location of DNA-associated proteins that are slated for degradation by the ubiquitin-proteasome system. The genome-wide map described here ties proteolysis in mammalian cells to active enhancers and to promoters of specific gene families. Nuclear-encoded mitochondrial genes in particular correlate with protein elimination, which positively affects their transcription. We show that the nuclear receptor corepressor NCoR1 is a key target of proteolysis and physically interacts with the transcription factor CREB. Proteasome inhibition stabilizes NCoR1 in a site-specific manner and restrains mitochondrial activity by repressing CREB-sensitive genes. In conclusion, this functional map of nuclear proteolysis links chromatin architecture with local protein stability and identifies proteolytic derepression as highly dynamic in regulating the transcription of genes involved in energy metabolism.Cell 12/2013; 155(6):1380-95. DOI:10.1016/j.cell.2013.11.016 · 33.12 Impact Factor